Analyzing the Short-term Effect of Placebo Therapy in Pulmonary Arterial Hypertension: Potential Implications for the Design of Future Clinical Trials

Abstract

Placebo is commonly used in short-term randomized trials for pulmonary arterial hypertension (PAH). Currently, outcome data regarding placebo are lacking. We conducted a systematic review and performed a metaanalysis to assess its effect. Articles were identified via a query of MEDLINE and EMBASE using the following terms: "pulmonary hypertension"; "clinical trial"; "six minute walk"; "pulmonary hemodynamic"; and "survival." A manual bibliography search of selected trials, reviews, and guidelines was performed. The inclusion criteria were as follows: randomized, placebo-controlled with data reported at baseline and at 12 to 18 weeks. Two reviewers independently abstracted: 6-min walk distance, pulmonary hemodynamic measures and frequency of death, clinical worsening, and change in New York Heart Association/World Health Organization functional class. The data were pooled using a random-effects model. Thirteen of the 688 articles identified met the inclusion criteria (a total of 868 placebo-treated patients). After 12 to 18 weeks, the 6-min walk distance decreased by 8.4 m (95% confidence interval [CI], -14.6 to -2.2) and pulmonary vascular resistance increased by 58.9 dyne (.) s (.) cm(-5) (95% CI, 27.6 to 90.1). Placebo-treated patients were 1.81 times more likely to experience a clinical worsening (95% CI, 1.30 to 2.53). Placebo treatment was not associated with a difference in mortality. Patients with PAH who receive placebo are more likely to experience clinical deteriorations. Further debate is needed regarding the design of future clinical trials. Research efforts should focus on evaluating existing medications against one another and comparing novel therapies with currently accepted ones.